Stimulus-responsive micellar carrier

ABSTRACT

A stimulus-responsive micellar carrier, methods that may be associated with making a stimulus-responsive micellar carrier, and methods that may be associated with using a stimulus-responsive micellar carrier are disclosed. The stimulus-responsive micellar carrier comprises a cargo molecule, and a linear block copolymer having a hydrophilic block connected to a hydrophobic block by a stimulus-responsive junction moiety. The micellar carrier can be supplied to a patient body for therapeutic purposes, such as the treatment of cancerous tissue. A method of preparing or obtaining a stimulus-responsive micellar carrier may include preparing a polyethylene glycol material having an acetal end group and then preparing a block copolymer by forming a reaction mixture including the polyethylene glycol material, a cyclic carbonate monomer, and a base.

BACKGROUND

The present disclosure relates, in general, to polymeric micelles withapplications as carriers or delivery vehicles for therapeutic agents orother small molecule cargo.

Polymeric micelles are considered promising carriers for therapeuticagents in medical applications. Several types of polymer micelles havealready been used in hospital settings or have been investigated inclinical trials. Micelles are aggregates of certain molecules that haveportions that are mutually attracted to each other. For example,polymeric chains having a hydrophobic end (tail) and a hydrophilic end(head) can aggregate, after an initial dispersal in a liquid, intonanostructured micelles via supramolecular interactions. A polymerincluding a hydrophobic block and a hydrophilic block may be referred toas an amphiphilic block copolymer. In general, amphiphilic blockcopolymers may spontaneously self-assemble into core-shell micelles inaqueous solutions when at a concentration above a critical concentrationlevel (the critical micelle concentration or CMC). The resulting micellehas hydrophilic exterior (shell) and a hydrophobic interior (core).Typical sizes of such micelles are on the order of a few nanometers toseveral hundred nanometers in diameter.

A micelle formed with an amphiphilic block copolymer can be “loaded”with a hydrophobic cargo during the assembly process. That is, a cargo,such as a hydrophobic small molecule, will tend to segregate into thehydrophobic core of the micelle. A micelle assembly incorporating acargo in association with its core region may be referred to as acarrier or, more particularly, a micellar carrier. In some instances,depending on dimension, such a micellar carrier may be referred to as ananocarrier, a nanoparticle, or a cargo delivery vehicle.

When a drug or therapeutic agent is “loaded” as cargo into a hydrophobiccore of the micelle, the hydrophilic shell can serve to protect thedrug/agent during transport to an intended target site within a patientsuch as a tumor or other diseased tissue site. However, a controlleddelivery or release of the cargo from the protected core regionspecifically at the intended target site is difficult to achieve.Furthermore, the therapeutic cargo will, in general, be less effectiveat the target site while still surrounded by the protective outer shell.Thus, it is usually preferable for the cargo to be released from thecarrier at the target site if possible.

BRIEF SUMMARY

According to an embodiment of the present disclosure, a method comprisesobtaining a micellar carrier that includes a block copolymer having ahydrophilic block connected to a hydrophobic block by astimulus-responsive junction moiety and a cargo molecule. The methodfurther includes supplying the micellar carrier to a patient body. Insome examples, the cargo molecule may be a therapeutic agent. In someexamples, the stimulus-responsive junction moiety may include an acetallinkage.

According to another embodiment of the present disclosure, a methodincludes preparing a polyethylene glycol material having an acetal endgroup and then preparing a block copolymer by forming a reaction mixtureincluding the polyethylene glycol material, a cyclic carbonate monomer,and a base. In some examples, the base may be an organobase, such as DBU(diazabicycloundecene) or the like. The polyethylene glycol material maybe derived from a linear polyethylene glycol in some examples.

According to still another embodiment of the present disclosure, amicellar carrier comprises a block copolymer having a hydrophilic blockconnected to a hydrophobic block by a stimulus-responsive junctionmoiety, and a cargo molecule that is hydrophobic. In some examples, themicellar carrier can be a nanocarrier. In some examples, the cargomolecule can be a therapeutic agent and the block copolymer maycorrespond the following chemical formula:

wherein n and m correspond to respective number of repeat units in theblock copolymer.

Various example embodiments will be described with reference to theaccompanying figures. The figures are schematic and/or conceptual and,unless otherwise noted, depictions are not intended to be at scale.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a general scheme for preparing core-shell micelle fordrug or therapeutic agent delivery.

FIG. 2 depicts a triggered release of a core-shell micelle for drug ortherapeutic agent delivery.

FIG. 3 depicts a block copolymer having a junction moiety which isstimuli responsive.

FIG. 4A depicts a synthesis of an acetal end-functionalized polyethyleneglycol.

FIG. 4B a synthesis of a block copolymer having an acetal junction froman acetal end-functionalized polyethylene glycol.

FIG. 5 depicts experimental results demonstrating (left side) linking ofblock copolymer having a stimuli-responsive junction moiety and (rightside) pH-induced chain scissioning of the block copolymer having thestimuli responsive junction moiety.

DETAILED DESCRIPTION

Micellar nanocarriers have been investigated as delivery vehicles fortherapeutic agents for medical applications. In general, a micellarnanocarrier is formed to incorporate drug molecules, therapeutic agents,or the like as cargo that is loaded in to the nanocarrier's core. Thenanocarrier incorporating the cargo can then be administered to apatient by various possible means, such as orally, intravenously,subcutaneously, etc. The nanocarrier protects the cargo from degradationin and/or elimination from the patient's body. In cases when, forexample, the cargo has high toxicity, the nanocarrier may also act toprotect the patient from adverse or unintended effects of the cargobeing released non-specifically within the body. Preferably, a hightoxicity cargo might only be released into the body at specific diseasedsites rather than broadly or non-specifically to all parts of the body.

Amongst many advantages, a targeted cargo release from a micellarcarrier allows for smaller total amounts of cargo to be supplied to apatient since it is unnecessary to dose the patient's entire body volumeto achieve therapeutic concentrations at the diseased site. Likewise,targeted release could limit damage that otherwise might be caused tohealthy tissue outside of the target site(s) that could be attendant toa general release of the cargo within the patient. The presentdisclosure describes methods and materials by which targeted release oftherapeutic cargos can be achieved using core-shell micelles asnanocarriers.

With reference now to FIG. 1, a scheme for preparing a core-shellmicelle for drug or therapeutic agent delivery is depicted. Anamphiphilic linear block copolymer 100 is prepared to include ahydrophobic block and a hydrophilic block. In this example, the blockcopolymer 100 is a diblock polymer including a hydrophilic block 110 anda hydrophobic block 120. The hydrophilic block 110 is linked to thehydrophobic block 120 by a stimuli-responsive junction moiety 130.

Once synthesized, the block copolymer 100 can be mixed in an aqueoussolution with a therapeutic agent 150, which in this instance ishydrophobic. When mixed in this manner, the block copolymer 100 and thetherapeutic agent 150 aggregate or self-assemble into micelle 160.Micelle 160 may also be referred to as a nanoparticle or a nanocarrierin some contexts. The therapeutic agent 150 can comprise therapeuticmolecules, drug compounds, proteins, DNA fragments, RNA fragments,and/or other molecules or compounds having bioactivity that might beused to treat diseases and/or conditions in a patient.

As depicted in FIG. 1, the core of micelle 160 is formed by thehydrophobic moieties (hydrophobic blocks) 120 of several blockcopolymers 100. The hydrophobic therapeutic agent(s) 150 (e.g., smallmolecules chemical compounds) can be loaded into core by supramolecularattractions between the hydrophobic components. Cargo loading capacityof polymeric micelle cargo carriers is mainly affected by theinteractions between the cargo component(s) and the micellar core. Assuch, either or both of the therapeutic agent 150 or the hydrophobicblocks 120 may be tailored to adjust load capacity. For example, thelength/size of the hydrophobic block 120 may be increased or decreasedto alter load capacity. The shell of the micelle 160 is formed by thehydrophilic moieties (hydrophilic blocks) 110. The hydrophilic shellprotects the therapeutic agent 150 associated with the core fromchemical and biological attack such as enzymatic degradation,opsonization by phagocytes and macrophages, and the like.

As depicted in FIG. 2, the stimuli-responsive junction moiety 130responds to environmental changes by de-linking the hydrophobic block120 from the hydrophilic block 110 of the micellar core region. That is,the response of the stimuli-responsive junction moiety 130 causescleaving of the amphiphilic block copolymer 100 into its componentblocks (e.g., blocks 110 and 120). The cleaving of the amphiphilic blockcopolymer 100 in effect destabilizes the micelle 160 and allows theouter shell (comprised of hydrophilic blocks 110) to disperse, leavingthe core (comprised of hydrophobic blocks 120) unprotected or exposed.

FIG. 2 depicts the therapeutic agents 150 (previously loaded within thecore region of micelle 160) as dispersing; however, such a physicaldispersal of the therapeutic agent(s) 150 is not a requirement and“release” of the therapeutic agent(s) 150 in this context may, in someinstances, consist only of an increase in exposure or availability ofthe therapeutic agents 150 that might accompany the release/dispersal ofthe shell of micelle 160. That is, therapeutic agent(s) 150 might remainaggregated with the remaining core of micelle 160 (the hydrophobicblocks 120) for an indefinite period of time after the cleaving ofamphiphilic copolymer 100.

It should be noted that dimensions and relative ratios of dimensions forthe sub-portions of micelle 160 depicted in FIG. 1 and FIG. 2 are notnecessarily to scale for an actual micelle 160. The depicted dimensionsof block copolymer 100 and therapeutic agent 150, along with the totalnumber of block copolymers 100 and therapeutic agents 150, withinmicelle 160 have been selected for purposes of explaining the generalarrangement of the various parts of micelle 160 rather than fordimensional or numerical correctness.

The total number (aggregation number) of block copolymers 100 withinmicelle 160 is not a limitation and may be any number that provides amicellar character to micelle 160. Likewise, the total number (loading)of the therapeutic agents 150 incorporated into micelle 160 is not alimitation and may be any number greater than one. It is also possiblefor micelle 160 to be provided for purposes of storage and/ortherapeutic delivery in a mixture with other micelles or micellarmaterials that incorporate no therapeutic agent 150. Likewise, when morethan one molecule of a therapeutic agent 150 is incorporated into amicelle 160, it is not a requirement that each such therapeutic agent150 be the same-type of molecule or compound. That is, a mixture ofdifferent therapeutic agents 150 may be incorporated into each micelle160. Similarly, a mixture of several different micelles 160 each havinga different therapeutic agent may be prepared and then administeredcollectively. Furthermore, it is not necessarily required for thestructure of micelle 160 to be composed exclusively of block copolymers100. That is, other amphiphilic copolymers lacking a stimulus-responsivejunction moiety 130 may be included in micelle 160 along with the blockcopolymers 100 to control or adjust release of the therapeutic agents150 after the junction severing triggering stimulus has beenencountered.

In general, though it is not necessarily a limitation, a micelle 160 maybe a nanoscale (˜10⁻⁹ m) to microscale (˜10⁻⁶ m) particle. In someexamples, the micelle 160 may have a diameter the range of 20 nm to 200nm. In this context, diameter refers to a hydrodynamic dimension asmeasured, for example, by a light scattering method, such as staticlight scattering (SLS) or dynamic light scattering (DLS), underconditions (e.g., pH, temperature, concentration) corresponding torelevant biological conditions. In a particular embodiment, thevolume-weighted average hydrodynamic diameter for a distribution ofmicelles 160 may be in the range of 20 nm to 200 nm for relevantbiological environmental conditions.

In a particular embodiment, the stimuli-responsive junction moiety 130is a pH-sensitive junction moiety. Thus, for this embodiment, thestimulus to which the stimuli-responsive junction moiety 130 respondsincludes a change in pH level of the micelle's surroundings. ThepH-sensitive junction moiety in this particular embodiment can includean acetal group, which is stable under basic and neutral conditions (pH≥7), but degrades under acidic conditions (pH ≤˜6.5).

Thus, in aqueous media at a neutral or physiological pH level (pH=˜7.4),such a block copolymer 100 can act as a surfactant and self-assembleinto a core-shell nanoparticle (e.g., a spherical micelle) 160. Duringthis self-assembly process, hydrophobic small molecules such as ananti-cancer drug (e.g., a therapeutic agent 150) can be incorporatedinto the micelle 160. In this context, micelle 160 may also be referredto as nanocarrier 160. This loaded nanocarrier 160 will be stable atneutral or physiological pH conditions, as long as its localconcentration remains above the CMC. However, upon exposure to low pHconditions, the acetal group of the junction moiety 130 will degrade,cleaving the hydrophilic shell from of the nanocarrier 160, therebyreleasing the cargo (e.g., therapeutic agent 150) loaded in the core ofthe nanocarrier 160.

Targeted Delivery

In micelle 160, the protective outer shell acts to increase, forexample, the time the therapeutic agent 150 remains unaffected by theelimination mechanisms and defenses of the patient's body. In addition,when micelle 160 has a size (diameter) of 20 nm-200 nm, it is largeenough to escape extravasation from normal vessel walls and avoidpremature elimination via the kidneys, but is generally small enough topermeate through leaky blood vessels and/or stay within the tumortissues having compromised lymphatic filtration. This effect isotherwise known as the enhanced permeation and retention (EPR) effect.Thus, in some example embodiments, micelle 160 has a diameter in a rangeof 20 nm to 200 nm to utilize the EPR effect. Targeted deliverystrategies, such as those that utilize the EPR effect, help reducesystemic toxicity of intravenously supplied therapeutic agents.

On the cellular level, nano-sized polymeric micelles offer anendocytosis internalization pathway allowing for easy cellular uptake.This nano-sizing helps overcome multidrug-resistance problems that mightbe caused by drug efflux mechanisms. Despite the numerous advantages ofmicellar drug delivery, several unmet challenges still exist withrespect to targeted delivery of therapeutic agents. For example, when adrug-loaded micelle reaches its target, the release of the cargo/payloadneeds to occur for the intended therapeutic effect to take place atmaximum efficiency. In other words, if the payload or therapeutic agentis retained inside the protected micellar core at the target site, theremay be little to no therapeutic activity caused by the cargo because itremains surrounded (encapsulated) by a protective outer shell of themicelle and thus substantially unavailable for purposes of biologicalactivity.

Mechanisms for cargo release at specific targets sites generally requiredestabilization of the micelle in one form or another. For instance,when the micelle is comprised of biodegradable polymers, then one canexpect diffusion-limited release kinetics of the cargo according to thebiodegradation rate of the polymer(s) forming the micelle. But in manyinstances it may be preferable for cargo release to be triggered by aspecific stimulus that is unique to (or at least more prevalent at) thetarget site. For example, it is known that the extracellularmicroenvironment of cancerous tissue is often more acidic (pH range ˜6.5to ˜6.9) than that of healthy tissue (pH ˜7.4). Thus, a cargo releasetriggered by a drop into the pH 6.5 to pH 6.9 range could be used toprovide selective cargo release from the micellar carrier at a canceroustarget site.

In a particular example, an amphiphilic polycarbonate-based blockcopolymer nanocarrier can be provided such that the micellar hydrophilicshell is discarded at low pH (such as in pH range 6.5 to 6.9), therebyfacilitating a stimuli-responsive cargo release mechanism fortherapeutic agent delivery to a diseased microenvironment within thebody.

FIG. 3 depicts a particular example of an amphiphilic block copolymer100. In this example, the hydrophilic block 110 is a polyethylene glycol(PEG) derived group, the hydrophobic block 120 is polycarbonate (PC)derived group, and the stimulus responsive junction moiety 130 is anacetal linkage. Many PEG materials are considered suitable for use inbiomedical applications and the depicted polycarbonate material isconsidered biodegradable. Thus, various copolymers of PEG and PC couldbe expected to be suitable for certain biomedical applications, such asmicellar nanocarriers.

Under acidic conditions, the acetal linkage in junction moiety 130breaks down into acetaldehyde and the corresponding alcohols. Note alsothat ketal moieties can be used as junction moiety 130. Ketal moietiesare similarly acid-sensitive as acetal moieties and have acetone andalcohols as decomposition products.

Though depicted as a linear polymer group, the PEG derived group may bebranched or incorporate other morphologies. Other groups/polymers may beappended or grafted to PEG backbone of the PEG-derived group. The numberof repeat units (n) in the PEG derived group may be varied inconjunction with the number of repeat units (m) of the PC derived groupto provide an appropriate size for micelle 160.

In other examples, the hydrophilic block 110 can be a polypropyleneglycol derived group or other polyether derived groups. Also, theamphiphilic block copolymer 100 is not limited to a diblock polymer andadditional blocks may be incorporated in some instances while preservingmicellar self-assembly by careful use of hydrophobic and hydrophiliccomponents. In other examples, the PC derived group may have a structurecorresponding to:

where R includes at least one carbon atom. In some examples, R may beone of a methyl group (—CH₃) or benzyl group (—CH₂C₆H₅). In otherexamples, R may be a derivate of a benzyl group, such as a benzyl groupwith a substituted benzene ring. In further examples, the R group may bean alkyl group, straight chain or branched, including 2 to 20 carbonatoms. The R group may incorporate a boronic acid functional groupR₁—B(OH)₂, where R₁ includes an attachment to the PC derived group. Rmay include or be a urea (carbamide)-type functional group,(R₁R₂N)CO(NR₃R₄), in which one of R₁-R₄ includes an attachment to the PCderived group, and, in general, R₁-R₄ may otherwise independently be ahydrogen atom (H) or include at least one carbon. The R group mayinclude or be a thiourea-type functional group, (R₁R₂N)CS(NR₃R₄), inwhich one of R₁-R₄ includes the attachment to the PC derived group, and,in general, R₁-R₄ may otherwise independently be a hydrogen atom (H) orinclude at least one carbon. In the above, R₁-R₄ may be alkyl groupsincluding 1-20 carbons, and R₁-R₄ may include additional functionalgroups beyond those mentioned. The R group may incorporate one or moreunsaturated groups, one or more cyclic groups, and one or moreheterocyclic groups. In general, the structure of the R group should beconsider limited only by any required synthetic compatibility with thepreparation of the cyclic carbonate monomer and the ring-openingpolymerization step (see FIG. 4B, described further below). It should benoted protection/de-protection of various functional groups which mightbe incorporated into the R group could be incorporated into thesynthetic scheme when required.

Synthesis of Amphiphilic Block Copolymers

FIG. 4A depicts a synthesis process for an acetal end-functionalizedpolyethylene glycol. In particular, synthesis of one example acetalend-functionalized PEG (PEG-a-OH) is shown in FIG. 4A. The synthesis ofPEG-a-OH is, in general, known. Here, a linear polyethylene glycolmaterial (mPEG) is reacted with 2-(vinyloxy)ethyl acetate to form anintermediate PEG material having an acetate end group. The number (n) ofrepeat units in the mPEG may be any suitable number greater than onewhich provides sufficient hydrophilicity to the ultimate end productblock copolymer to provide a micellar carrier 160 at the appropriatedimension. As depicted, this step utilizes a catalytic amount ofp-toluene sulfonic acid (TsOH). Base catalyzed hydrolysis of theintermediate PEG material provides the PEG-a-OH material.

In FIG. 4A, the 2-(vinyloxy)ethyl acetate is depicted as being formed bythe reaction of ethylene glycol vinyl ether (IUPAC: 2-(vinyloxy)ethanol)and acetic anhydride (Ac₂O). Other synthetic routes to PEG-a-OH areavailable and the process of FIG. 4A is provided as one possible route.Unless otherwise indicated, all chemical reactions described herein maybe performed at ambient conditions or under mild heating in a suitablesolvent.

FIG. 4B depicts the synthesis of a pH-sensitive block copolymer byDBU-catalyzed ring-opening polymerization (ROP) of a cyclic carbonatemonomer (MTC-OBn) using PEG-a-OH (from FIG. 4A) as a polymerizationinitiator. Here, DBU (1,8-diazabicycloundec-7-ene) is an organobase thatis non-nucleophilic. MTC-OBn is 2-benzyloxycarbonyl-2-methyltrimethylenecarbonate. Here, the benzyl group is an example of the R group discussedin conjunction with explanation of the PC derived group above. Ingeneral, the benzyl group may be replaced in accordance with thedescription of the R group provided above.

Other bases with similar characteristics to DBU might be adopted in thiscontext. A solvent, such as dichloromethane (CH₂Cl₂), is used in thereaction mixture. The reaction can be conducted at room temperature.

The acetal functional group present in the PEG-a-OH material iscompatible with the basic ROP conditions described here. Successful ROPto afford PEG-a-poly(MTC-OBn) was confirmed by gel permeationchromatography (GPC), as shown in FIG. 5 (left panel). The number (m) ofrepeat units of the carbonate group in the end product(PEG-a-poly(MTC-OBn) can be any suitable number greater than one whichprovides sufficient hydrophobicity to the end product block copolymer toprovide a micellar carrier 160 at the appropriate dimensions.

As noted, successful formation of PEG-a-poly(MTC-OBn) is established bythe shifting of GPC test peaks to shorter retention time (all otherthings being equal, larger molecules are retained for shorter times thansmaller molecules) as shown in FIG. 5 (left side). The acid-induceddegradation of PEG-a-poly(MTC-OBn) in an organic solvent is shown inFIG. 5 (right panel). Treating a dichloromethane (CH₂Cl₂) solution ofthe PEG-a-poly(MTC-OBn) with trifluoroacetic acid (TFA) at roomtemperature resulted in a significant loss in intensity of the GPCsignal attributable to the block copolymer (at shorter retention times)and the appearance of a new signal shifted toward lower molecularweights (longer retention times). This result is consistent withcleavage of the block copolymer at the acetal junction.

The descriptions of the various embodiments of the present disclosurehave been presented for purposes of illustration, but are not intendedto be exhaustive or limited to the embodiments disclosed. Manymodifications and variations will be apparent to those of ordinary skillin the art without departing from the scope and spirit of the describedembodiments. The terminology used herein was chosen to best explain theprinciples of the embodiments, the practical application or technicalimprovement over technologies found in the marketplace, or to enableothers of ordinary skill in the art to understand the embodimentsdisclosed herein.

What is claimed is:
 1. A method of using a micellar carrier, comprising:preparing a micellar carrier, the micellar carrier comprising: a cargomolecule, and a linear block copolymer consisting of a hydrophilic blockcomprising a polyethylene glycol, a hydrophobic block having a structurecomprising a carbonate group, and a stimulus-responsive junction moietyhaving the structure

wherein one wavy bond represents a bond directly connected to thepolyethylene glycol of the hydrophilic block and the other wavy bondrepresents a bond directly connected to the carbonate group of thehydrophobic block; and supplying the micellar carrier to a patient body.2. The method of claim 1, wherein the cargo molecule is a therapeuticagent.
 3. The method of claim 1, wherein supplying the micellar carrieris performed via intravenous injection.
 4. The method of claim 1,wherein the cargo molecule is an anti-cancer compound.
 5. The method ofclaim 1, wherein the micellar carrier has a diameter between 20 nm and200 nm.
 6. The method of claim 1, wherein preparing the micellar carriercomprises: preparing the hydrophilic block having an acetal end group;and preparing the linear block copolymer by forming a reaction mixtureincluding the hydrophilic block, a cyclic carbonate monomer, and a base.7. A method of using a micellar carrier, comprising: preparing amicellar carrier, wherein the micellar carrier is a nanoscale (10⁻⁹ m)to microscale (10⁻⁶ m) particle, the micellar carrier comprising: atherapeutic agent, and a linear block copolymer consisting of ahydrophilic block connected to a hydrophobic block by astimulus-responsive junction moiety having the structure

wherein: the hydrophilic block comprises a polyethylene glycol, thehydrophobic block comprises a carbonate group, one wavy bond representsa bond directly connected to the polyethylene glycol of the hydrophilicblock and the other wavy bond represents a bond directly connected tothe carbonate group of the hydrophobic block; and supplying the micellarcarrier to a patient body.
 8. The method of claim 7, wherein supplyingthe micellar carrier is performed via intravenous injection.
 9. Themethod of claim 7, wherein the therapeutic agent is an anti-cancercompound.
 10. The method of claim 7, wherein the micellar carrier has adiameter between 20 nm and 200 nm.
 11. The method of claim 7, whereinpreparing a micellar carrier comprises: preparing a polyethylene glycolmaterial having an acetal end group; and preparing the linear blockcopolymer by forming a reaction mixture including the polyethyleneglycol material, a cyclic carbonate monomer, and a base.
 12. A method ofusing a micellar carrier, comprising: preparing a micellar carriercomprising preparing a polyethylene glycol material having an acetal endgroup, and preparing a linear block copolymer by forming a reactionmixture including a polyethylene glycol material, a cyclic carbonatemonomer, and a base, wherein the micellar carrier is a nanoscale (10⁻⁹m) to microscale (10⁻⁶ m) particle, the micellar carrier comprising: acargo molecule, and a linear block copolymer consisting of a hydrophilicblock connected to a hydrophobic block by a stimulus-responsive junctionmoiety having the structure

wherein: the hydrophilic block comprises a polyethylene glycol, thehydrophobic block comprises a carbonate group, one wavy bond representsa bond directly connected to the polyethylene glycol of the hydrophilicblock and the other wavy bond represents a bond directly connected tothe carbonate group of the hydrophobic block; and supplying the micellarcarrier to a patient body.
 13. The method of claim 12, wherein the cargomolecule is a therapeutic agent.
 14. The method of claim 12, whereinsupplying the micellar carrier is performed via intravenous injection.15. The method of claim 12, wherein the cargo molecule is an anti-cancercompound.
 16. The method of claim 12, wherein the micellar carrier has adiameter between 20 nm and 200 nm.
 17. The method of claim 1, whereinthe structure of the hydrophobic block further comprises an R group,wherein the R group is one of a methyl group, a benzyl group, a derivateof a benzyl group, a linear alkyl group having 2 to 20 carbon atoms, abranched alkyl group having 2 to 20 carbon atoms, a carbamide grouphaving the chemical formula (R₁R₂N)CO(NR₃R₄), or a thiourea group havingthe chemical formula (R₁R₂N)CS(NR₃R₄), wherein each of R₁, R₂, R₃, andR₄ is independently a hydrogen or a group that includes at least onecarbon atom.
 18. The method of claim 1, wherein the structure of thehydrophobic block further comprises an R group, wherein the R groupincludes a boronic acid functional group, a carbamide group having thechemical formula (R₁R₂N)CO(NR₃R₄), a thiourea group having the chemicalformula (R₁R₂N)CS(NR₃R₄), one or more unsaturated groups, one or morecyclic groups, or one or more heterocyclic groups, wherein each of R₁,R₂, R₃, and R₄ is independently a hydrogen or a group that includes atleast one carbon atom.
 19. The method of claim 1, wherein the structureof the hydrophobic block further comprises an R group, wherein the Rgroup is one of a methyl group or a benzyl group.
 20. The method ofclaim 7, wherein the structure of the hydrophobic block furthercomprises an R group, wherein the R group is one of a methyl group or abenzyl group.